The underlying premise of this work is that inhibition of proteolysis observed during aging results in an inhibition of cell proliferation responses, as exemplified by reduced immune function, liver regeneration, and wound-healing. In this proposal, it is hypothesized that inhibition of cysteine proteinases by thiostatin results in impairment in the cell's ability to respond to mitogenic stimuli. To test this, it is proposed to identify: (1) the site(s) within the cell cycle that are affected by thiostatin overexpression, and (2) the molecular mechanisms responsible for inhibition of the MAP kinase pathway of signal transduction in thiostatin-producing cells.